TIM recognition of phosphatidylserine regulates innate and adaptive immunity

Dana-Farber Cancer Inst, Boston MA

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Abstract

The TIM family of genes consists of eight members {TIM-1-8) on mouse chromosome 11B1.1, and three members {Tlf\/I1, TIMS, and TIM4) on human chromosome 5q33.2 (5). All ofthe mouse and human TIM genes encode type 1 membrane proteins, consisting of an N-terminal Cys-rich IgV-like domain, a mucin-like domain, a transmembrane domain, and an intracellular tail (Figure 1). The intracellular tails of TIM-1, TIM-2, and TIM-3, but not TIM-4, contain predicted tyrosine phosphorylation motifs, suggesting that these TIMs are involved in transmembrane signaling. Whereas TIM-3 has only three predicted glycosylation sites, human TIM-1 has 60, which are primarily 0-linked glycosylation motifs located within the mucin-like domain. The N-terminal Cys-rich regions ofthe TIM homologs have a sequence identity of about 40%, whereas sequence identity between the mouse and human orthologs is around 60% (6). The structural similarities between all the TIMs suggest that they arose from an ancestral gene by successive gene duplication events. TIM-1 polymorphisms and protection against asthma and allergy. Human TIM-1 (HUGO designation HAVCR1) is highly polymorphic in humans and monkeys, as it is in mice, with single nucleotide polymorphisms (SNPs) as well as insertion/deletion variants occurring primarily in the mucin-like domain in both mice and humans (as defined in the previous Project 1). We have also performed association analysis ofthe insertion/deletion variants of TIM-1 in